14-100732047-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003836.7(DLK1):​c.268C>T​(p.Arg90Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,178 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DLK1
NM_003836.7 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17
Variant links:
Genes affected
DLK1 (HGNC:2907): (delta like non-canonical Notch ligand 1) This gene encodes a transmembrane protein that contains multiple epidermal growth factor repeats that functions as a regulator of cell growth. The encoded protein is involved in the differentiation of several cell types including adipocytes. This gene is located in a region of chromosome 14 frequently showing unparental disomy, and is imprinted and expressed from the paternal allele. A single nucleotide variant in this gene is associated with child and adolescent obesity and shows polar overdominance, where heterozygotes carrying an active paternal allele express the phenotype, while mutant homozygotes are normal. [provided by RefSeq, Nov 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DLK1NM_003836.7 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 4/5 ENST00000341267.9 NP_003827.4
DLK1NM_001317172.2 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 4/6 NP_001304101.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DLK1ENST00000341267.9 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 4/51 NM_003836.7 ENSP00000340292 P1P80370-1
DLK1ENST00000331224.10 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 4/61 ENSP00000331081 P80370-2
DLK1ENST00000392848.9 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 6/64 ENSP00000376589

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
249530
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
134982
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000293
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.0000658
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1459986
Hom.:
0
Cov.:
29
AF XY:
0.0000110
AC XY:
8
AN XY:
726234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000581
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
31
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2023The c.268C>T (p.R90W) alteration is located in exon 4 (coding exon 4) of the DLK1 gene. This alteration results from a C to T substitution at nucleotide position 268, causing the arginine (R) at amino acid position 90 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.028
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.35
T;D;D;.
Eigen
Uncertain
0.27
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;.;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Uncertain
0.65
D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.3
.;M;M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.28
T
PROVEAN
Uncertain
-4.3
D;D;.;D
REVEL
Uncertain
0.43
Sift
Uncertain
0.0050
D;D;.;D
Sift4G
Uncertain
0.028
D;D;.;D
Polyphen
1.0
.;D;D;D
Vest4
0.42, 0.41
MutPred
0.53
Gain of catalytic residue at S94 (P = 0.0014);Gain of catalytic residue at S94 (P = 0.0014);Gain of catalytic residue at S94 (P = 0.0014);Gain of catalytic residue at S94 (P = 0.0014);
MVP
0.95
MPC
1.1
ClinPred
0.70
D
GERP RS
3.6
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.8
Varity_R
0.33
gMVP
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs755858246; hg19: chr14-101198384; COSMIC: COSV57993078; COSMIC: COSV57993078; API